External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection
Authors: Bernard Surial, Adrià Ramírez Mena, Marie Roumet, Andreas Limacher, Colette Smit, Olivier Leleux, Amanda Mocroft, Marc van der Valk, Fabrice Bonnet, Lars Peters, Jürgen K. Rockstroh, Huldrych F. Günthard, Annalisa Berzigotti, Andri Rauch, Gilles Wandeler, I. Abela, K. Aebi-Popp, A. Anagnostopoulos, M. Battegay, E. Bernasconi, D.L. Braun, H.C. Bucher, A. Calmy, M. Cavassini, A. Ciuffi, G. Dollenmaier, M. Egger, L. Elzi, J. Fehr, J. Fellay, H. Furrer, C.A. Fux, H.F. Günthard, A. Hachfeld, D. Haerry, B. Hasse, H.H. Hirsch, M. Hoffmann, I. Hösli, M. Huber, D. Jackson-Perry, C.R. Kahlert, L. Kaiser, O. Keiser, T. Klimkait, R.D. Kouyos, H. Kovari, K. Kusejko, N. Labhardt, K. Leuzinger, Martinez de Tejada B, C. Marzolini, K.J. Metzner, N. Müller, J. Nemeth, D. Nicca, J. Notter, P. Paioni, G. Pantaleo, M. Perreau, A. Rauch, L. Salazar-Vizcaya, P. Schmid, R. Speck, M. Stöckle, P. Tarr, A. Trkola, G. Wandeler, M. Weisser, S. Yerly, M. van der Valk, S.E. Geerlings, A. Goorhuis, V.C. Harris, J.W. Hovius, B. Lempkes, F.J.B. Nellen, T. van der Poll, J.M. Prins, V. Spoorenberg, M. van Vugt, W.J. Wiersinga, F.W.M.N. Wit, C. Bruins, J. van Eden, I.J. Hylkema-van den Bout, A.M.H. van Hes, F.J.J. Pijnappel, S.Y. Smalhout, A.M. Weijsenfeld, N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel, K.C. Wolthers, H.L. Zaaijer, E.J.G. Peters, M.A. van Agtmael, R.S. Autar, M. Bomers, K.C.E. Sigaloff, M. Heitmuller, L.M. Laan, N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel, K.C. Wolthers, H.L. Zaaijer, M. van den Berge, A. Stegeman, S. Baas, L. Hage de Looff, A. van Arkel, J. Stohr, B. Wintermans, M.J.H. Pronk, H.S.M. Ammerlaan, E.S. de Munnik, B. Deiman, A.R. Jansz, V. Scharnhorst, J. Tjhie, M.C.A. Wegdam, M. van der Valk, A. van Eeden, E. Hoornenborg, J. Nellen, W. Alers, L.J.M. Elsenburg, H. Nobel, C.J. Schinkel, M.E.E. van Kasteren, M.A.H. Berrevoets, A.E. Brouwer, B.A.F.M. de Kruijf-van de Wiel, A. Adams, M. Pawels-van Rijkevoorsel, B.A.F.M. de Kruijf-van de Wiel, A.G.M. Buiting, J.L. Murck, C. Rokx, A.A. Anas, H.I. Bax, E.C.M. van Gorp, M. de Mendonça Melo, E. van Nood, J.L. Nouwen, B.J.A. Rijnders, C.A.M. Schurink, L. Slobbe, T.E.M.S. de Vries-Sluijs, N. Bassant, J.E.A. van Beek, M. Vriesde, L.M. van Zonneveld, J. de Groot, J.J.A. van Kampen, M.P.G. Koopmans, J.C. Rahamat-Langendoen, J. Branger, R.A. Douma, A.S. Cents-Bosma, C.J.H.M. Duijf-van de Ven, E.F. Schippers, C. van Nieuwkoop, J. Geilings, S. van Winden, G. van der Hut, N.D. van Burgel, E.M.S. Leyten, L.B.S. Gelinck, F. Mollema, G.S. Wildenbeest, T. Nguyen, P.H.P. Groeneveld, J.W. Bouwhuis, A.J.J. Lammers, A.G.W. van Hulzen, S. Kraan, M.S.M. Kruiper, G.L. van der Bliek, P.C.J. Bor, S.B. Debast, G.H.J. Wagenvoort, A.H.E. Roukens, M.G.J. de Boer, H. Jolink, M.M.C. Lambregts, H. Scheper, W. Dorama, N. van Holten, E.C.J. Claas, E. Wessels, J.G. den Hollander, R. El Moussaoui, K. Pogany, C.J. Brouwer, D. Heida-Peters, E. Mulder, J.V. Smit, D. Struik-Kalkman, T. van Niekerk, O. Pontesilli, C. van Tienen, S.H. Lowe, A.M.L. Oude Lashof, D. Posthouwer, M.E. van Wolfswinkel, R.P. Ackens, K. Burgers, M. Elasri, J. Schippers, T.R.A. Havenith, M. van Loo, M.G.A. van Vonderen, L.M. Kampschreur, M.C. van Broekhuizen, None S, None Faber, A. Al Moujahid, G.J. Kootstra, C.E. Delsing, M. van der Burg-van de Plas, L. Scheiberlich, W. Kortmann, G. van Twillert, R. Renckens, J. Wagenaar, D. Ruiter-Pronk, F.A. van Truijen-Oud, J.W.T. Cohen Stuart, M. Hoogewerf, W. Rozemeijer, J.C. Sinnige, K. Brinkman, G.E.L. van den Berk, K.D. Lettinga, M. de Regt, W.E.M. Schouten, J.E. Stalenhoef, J. Veenstra, S.M.E. Vrouenraets, H. Blaauw, G.F. Geerders, M.J. Kleene, M. Knapen, M. Kok, I.B. van der Meché, A.J.M. Toonen, S. Wijnands, E. Wttewaal, D. Kwa, T.J.W. van de Laar, R. van Crevel, K. van Aerde, A.S.M. Dofferhoff, S.S.V. Henriet, H.J.M. ter Hofstede, J. Hoogerwerf, O. Richel, M. Albers, K.J.T. Grintjes-Huisman, M. de Haan, M. Marneef, M. McCall, D. Burger, E.H. Gisolf, M. Claassen, R.J. Hassing, G. ter Beest, P.H.M. van Bentum, M. Gelling, Y. Neijland, C.M.A. Swanink, M. Klein Velderman, S.F.L. van Lelyveld, R. Soetekouw, L.M.M. van der Prijt, J. van der Swaluw, J.S. Kalpoe, A. Wagemakers, A. Vahidnia, F.N. Lauw, D.W.M. Verhagen, M. van Wijk, W.F.W. Bierman, M. Bakker, R.A. van Bentum, M.A. van den Boomgaard, J. Kleinnijenhuis, E. Kloeze, A. Middel, D.F. Postma, H.M. Schenk, Y. Stienstra, M. Wouthuyzen-Bakker, A. Boonstra, H. de Jonge, M.M.M. Maerman, D.A. de Weerd, K.J. van Eije, M. Knoester, C.C. van Leer-Buter, H.G.M. Niesters, None T.Mudrikova, R.E. Barth, A.H.W. Bruns, P.M. Ellerbroek, M.P.M. Hensgens, J.J. Oosterheert, E.M. Schadd, A. Verbon, B.J. van Welzen, H. Berends, B.M.G. Griffioen-van Santen, I. de Kroon, F.M. Verduyn Lunel, A.M.J. Wensing, M. van der Valk, S. Zaheri, A.C. Boyd, D.O. Bezemer, A.I. van Sighem, C. Smit, F.W.M.N. Wit, M.M.J. Hillebregt, T.J. Woudstra, T. Rutkens, D. Bergsma, N.M. Brétin, K.J. Lelivelt, L. van de Sande, K.M. Visser.S.T. van der Vliet, F. Paling, L.G.M. de Groot-Berndsen, M. van den Akker, R. Alexander, Y. Bakker, A. El Berkaoui, M. Bezemer-Goedhart, E.A. Djoechro, M. Groters, L.E. Koster, C.R.E. Lodewijk, E.G.A. Lucas, L. Munjishvili, B.M. Peeck, C.M.J. Ree, R. Regtop, A.F. van Rijk, Y.M.C. Ruijs-Tiggelman, P.P. Schnörr, M.J.C. Schoorl, E.M. Tuijn, D.P. Veenenberg, E.C.M. Witte, D. Bergsma, N.M. Brétin, Y.M.C. Ruijs-Tiggelman, I. Karpov, M. Losso, J. Lundgren, J. Rockstroh, I. Aho, L.D. Rasmussen, P. Novak, G. Wandeler, C. Pradier, N. Chkhartishvili, R. Matulionyte, C. Oprea, J.D. Kowalska, J. Begovac, J.M. Miró, G. Guaraldi, R. Paredes, G. Wandeler, R. Paredes, L. Peters, L. Peters, J.F. Larsen, B. Neesgaard, N. Jaschinski, O. Fursa, D. Raben, D. Kristensen, A.H. Fischer, S.K. Jensen, T.W. Elsing, M. Gardizi, A. Mocroft, A. Phillips, J. Reekie, A. Cozzi-Lepri, A. Pelchen-Matthews, A. Roen, E.S. Tusch, W. Bannister, P. Bellecave, P. Blanco, F. Bonnet, S. Bouchet, D. Breilh, C. Cazanave, S. Desjardin, V. Gaborieau, A. Gimbert, M. Hessamfar, L. Lacaze-Buzy, D. Lacoste, M.E. Lafon, E. Lazaro, O. Leleux, F. Le Marec, G. Le Moal, D. Malvy, L. Marchand, P. Mercié, D. Neau, I. Pellegrin, A. Perrier, V. Petrov-Sanchez, M.O. Vareil, L. Wittkop, N. Bernard, F. Bonnet, D. Bronnimann H. Chaussade, D. Dondia, P. Duffau, I. Faure, M. Hessamfar, P. Mercié, P. Morlat, E. Mériglier, F. Paccalin, E. Riebero, C. Rivoisy, M.A. Vandenhende, L. Barthod, C. Cazanave, F.A. Dauchy, A. Desclaux, M. Ducours, H. Dutronc, A. Duvignaud, J. Leitao, M. Lescure, D. Neau, D. Nguyen, D. Malvy, T. Pistone, M. Puges, G. Wirth, C. Courtault, F. Camou, C. Greib, E. Lazaro, J.L. Pellegrin, E. Rivière, J.F. Viallard, Y. Imbert, M. Thierry-Mieg, P. Rispal, O. Caubet, H. Ferrand, S. Tchamgoué, S. Farbos, M.O. Vareil, H. Wille, K. Andre, L. Caunegre, Y. Gerard, F. Osorio-Perez, I. Chossat, G. Iles, Y. Gerard, M. Labasse-Depis, F. Lacassin, A. Barret, C. Courtault, B. Castan, J. Koffi, N. Rouanes, A. Saunier, J.B. Zabbe, G. Dumondin, V. Gaborieau, Y. Gerard, G. Beraud, G. Le Moal, M. Catroux, M. Garcia, V. Giraud, J.P. Martellosio, F. Roblot, T. Pasdeloup, A. Riché, M. Grosset, S. Males, C. Ngo Bell, T. Pasdeloup, P. Blanco, I. Pellegrin, C. Carpentier, I. Pellegrin, Virology P. Bellecave, M.E. Lafon, C. Tumiotto, S. Bouchet, D. Breilh, G. Miremeont-Salamé, D. Arma, G. Arnou, M.J. Blaizeau, P. Camps, M. Decoin, S. Delveaux, F. Diarra, L. Gabrea, S. Lawson-Ayayi, E. Lenaud, D. Plainchamps, A. Pougetoux, B. Uwamaliya, K. Zara, V. Conte, M. Gapillout, O. Leleux, F. Le Marec, A. Perrier
Journal: Journal of Hepatology (2023)

Background & AimsHepatitis B virus (HBV) coinfection is common among people living with HIV (PLWH) and the most important cause of hepatocellular carcinoma (HCC). Whereas risk prediction tools for HCC exist for patients with HBV monoinfection, they have not been evaluated in PLWH. We performed an external validation of PAGE-B in people with HIV/HBV coinfection.MethodsWe included PLWH with a positive HBsAg and without HCC before starting tenofovir from four European cohorts, and estimated the predictive performance of PAGE-B on HCC occurrence over 15 years of tenofovir-containing antiretroviral therapy (ART). Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing cumulative incidences with the PAGE-B derivation study using Kaplan-Meier curves.ResultsIn total, 2'963 individuals with HIV/HBV coinfection on tenofovir-containing ART were included. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1000 patient-years, 95% confidence interval [CI] 2.03–3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61–1.25), and the pooled c-index was 0.77 (range 0.73–0.80), both indicating good model discrimination. Cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value for developing HCC within 5 years of 99.4%. Restricting efforts to individuals with a PAGE-B of ≥10 would spare HCC screening in 27% of individuals.ConclusionsFor individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening.IMPACT AND IMPLICATIONSChronic hepatitis B virus (HBV) infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV, and valid risk prediction may guide HCC screening efforts to high-risk individuals. We aimed at validating PAGE-B, a risk prediction tool that is based on age, gender, and platelets, among 2963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of less than 10 had a negative predictive value for developing HCC within 5 years of 99.4%. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.